Mesalazine controlled release oral pharmaceutical compositions

ABSTRACT

Controlled-release oral pharmaceutical compositions containing as active ingredient 5-amino-salicylic acid, comprising: a) an inner lipophilic matrix consisting of substances with a melting point below 90° C. in which the active ingredient is at least partly inglobated; b) an outer hydrophilic matrix in which the lipophilic matrix is dispersed; c) optionally other excipients.

The present invention relates to controlled release oral pharmaceuticalcompositions containing as active ingredient 5-amino salicylic acid,also named mesalazine.

BACKGROUND OF THE INVENTION

Mesalazine is used in the treatment of Chron's disease and ulcerativecolitis thanks to its antiinflammatory activity on the intestinalmucuses. Controlled-release formulations of mesalazine are disclosed inWO 95/16451, EP 0 453 001, EP 0 377 477.

The preparation of a sustained, controlled, delayed or anyhow modifiedrelease form can be carried out according to different known techniques:

1. The use of inert matrices, in which the main component of the matrixstructure opposes some resistance to the penetration of the solvent dueto the poor affinity towards aqueous fluids; such property being knownas lipophilia.

2. The use of hydrophilic matrices, in which the main component of thematrix structure opposes high resistance to the progress of the solvent,in that the presence of strongly hydrophilic groups in its chains,mainly branched, remarkably increases viscosity inside the hydratedlayer.

3. The use of bioerodible matrices, which are capable of being degradedby the enzymes of some biological compartment.

All the procedures listed above suffer, however, from drawbacks andimperfections.

Inert matrices, for example, generally entail non-linear, butesponential, release of the active ingredient.

Hydrophilic matrices have a linear behaviour until a certain fraction ofactive ingredient has been released, then they significantly deviatefrom linear release.

Bioerodible matrices are ideal to carry out the so-called“site-release”, but they involve the problem of finding the suitableenzyme or reactive to degradation. Furthermore, they frequently releasein situ metabolites that are not wholly toxicologically inert.

A number of formulations based on inert lipophilic matrices have beendescribed: Drug Dev. Ind. Pharm. 13 (6), 1001-1022, (1987) discloses aprocess making use of varying amounts of colloidal silica as aporization element for a lipophilic inert matrix in which the activeingredient is incorporated.

The same notion of canalization of an inert matrix is described in U.S.Pat. No. 4,608,248 in which a small amount of a hydrophilic polymer ismixed with the substances forming an inert matrix, in a non sequentialcompenetration of different matrix materials.

EP 375,063 discloses a technique for the preparation of multiparticulategranules for the controlled-release of the active ingredient whichcomprises co-dissolution of polymers or suitable substances to form ainert matrix with the active ingredient and the subsequent deposition ofsaid solution on an inert carrier which acts as the core of the device.Alternatively, the inert carrier is kneaded with the solution containingthe inert polymer and the active ingredient, then the organic solventused for the their dissolution is evaporated off to obtain a solidresidue. The resulting structure is a “reservoir”, i.e. is notmacroscopically homogeneous along all the symmetry axis of the finalform.

The same “reservoir” structure is also described in Chem. Pharm. Bull.46 (3), 531-533, (1998) which improves the application through anannealing technique of the inert polymer layer which is deposited on thesurface of the pellets.

To the “reservoir” structure also belong the products obtained accordingto the technique described in WO 93/00889 which discloses a process forthe preparation of pellets in hydrophilic matrix which comprises:

dissolution of the active ingredient with gastro-resistant hydrophilicpolymers in organic solvents;

drying of said suspension;

subsequent kneading and formulation of the pellets in a hydrophilic orlipophilic matrix without distinction of effectiveness between the twotypes of application.

EP 0 453 001 discloses a multiparticulate with “reservoir” structureinserted in a hydrophilic matrix. The basic multiparticulate utilizestwo coating membranes to decrease the release rate of the activeingredient, a pH-dependent membrane with the purpose of gastricprotection and a pH-independent methacrylic membrane with the purpose ofslowing down the penetration of the aqueous fluid.

WO 95/16451 discloses a composition only formed by a hydrophilic matrixcoated with a gastro-resistant film for controlling the dissolution rateof mesalazine.

When preparing sustained-, controlled-release dosage forms of amedicament topically active in the gastrointestinal tract, it isimportant to ensure a controlled release from the first phases followingadministration, i.e. when the inert matrices have the maximum releaserate inside the logarithmic phase, namely the higher deviation fromlinear release.

Said object has been attained by the present invention, which alsoallows to prepare compositions characterized by a high content in activeingredient.

DISCLOSURE OF THE INVENTION

The invention provides controlled release oral pharmaceuticalcompositions containing 5-amino-salicylic acid as the active ingredient,comprising:

a) an inner lipophilic matrix consisting of substances with meltingpoint below 90° C. in which the active ingredient is at least partiallyinglobated;

b) an outer hydrophilic matrix in which the lipophilic matrix isdispersed;

c) optionally other excipients.

DETAILED DISCLOSE OF THE INVENTION

The compositions of the invention can be obtained with a methodcomprising the following steps:

a) the active ingredient is first inglobated in a low melting excipientor mixture of excipients, while heating to soften and/or melt theexcipient itself, which thereby incorporates the active ingredient bysimple dispersion.

After cooling at room temperature an inert matrix forms, which can bereduced in size to obtain matrix granules containing the activeingredient particles.

b) the inert matrix granules are subsequently mixed together with one ormore hydrophilic water-swellable excipients.

This way, when the tablet is contacted with biological fluids, a highviscosity swollen layer is formed, which coordinates the solventmolecules and acts as a barrier to penetration of the aqueous fluiditself inside the new structure. Said barrier antagonizes the starting“burst effect” caused by the dissolution of the medicament inglobatedinside the inert matrix, which is in its turn inside the hydrophilicmatrix.

The lipophilic matrix consists of substances selected from unsaturatedand/or hydrogenated fatty acids, salts, esters or amides thereof, fattyacids mono-, di- or triglycerids, waxes, ceramides, cholesterolderivatives or mixtures thereof having melting point within the range of40 to 90° C.

If desired, a fatty acid calcium salt may be incorporated. in thelipophilic matrix which is subsequently dispersed in a hydrophilicmatrix prepared with alginic acid, thus remarkably increasing thehydrophilic matrix viscosity following penetration of the solvent frontuntil contact with the lipophilic matrix granules dispersed inside.

The weight content of the active ingredient in the lipophilic matrixusually ranges from 5 to 95%.

The inert lipophilic matrix is reduced into granules by an extrusionand/or granulation process, or any other known processes which retainthe homogeneous dispersion and matrix structure of the starting mixture.

The hydrophilic matrix consists of excipients known as hydrogels, i.e.substances which pass from the dry state to the hydrated one, undergothe so-called “molecular relaxation”, namely a remarkable increase inmass and weight following the coordination of a large number of watermolecules by the polar groups present in the polymeric chains of theexcipients themselves.

Examples of hydrogels which can be used according to the invention arecompounds selected from polymers or copolymers of acrylic or methacrylicacid, alkylvinyl polymers, hydroxyalkyl celluloses, carboxyalkylcelluloses, polysaccharides, dextrins, pectins, starches andderivatives, natural or synthetic gums, alginic acid.

The lipophilic matrix granules containing the active ingredient aremixed the with hydrophilic compounds cited above in a weight ratiotypically ranging from 100:0.5 to 100:20 (lipophilic matrix: hydrophilicmatrix). Part of mesalazine can optionally be mixed with hydrophilicsubstances to provide compositions in which the active ingredient isdispersed both in the lipophilic and the hydrophilic matrix, saidcomoositions being preferably in the form of tablets, capsules and/orminitablets.

The compression of the mixture of lipophilic matrix, hydrogel-formingcompounds and, optionally, active ingredient non inglobated in thelipophilic matrix, yields a macroscopically homogeneous structure in allits volume, namely a matrix containing a dispersion of the lipophilicgranules in a hydrophilic matrix.

The tablets, capsules and/or minitablets obtainable according to theinvention can optionally be subjected to known coating processes with agastro-resistant film, consisting of for example polymers of methacrylicacids (Eudragit^((R))) or cellulose derivatives, such as celluloseacetophthalate.

The compositions of the invention can contain a high percentage ofactive ingredient compared with the total composition weight up to 95%,an advantageous characteristic in the case of mesalazine which requiresrather high unitary doses.

In terms of dissolution characteristics, the compositions of theinvention provide a release profile of the active ingredient morehomogeneous than the traditional systems. In fact, the immediatepenetration of water inside the superficial layer of the hydrophilicmatrix and the consequent swelling due to the distension of thepolymeric chains of the hydrogels, gives rise to a high viscosityhydrated front which prevents the further penetration of water, linearlyslowing down the dissolution process to a well determined point whichcan be located at about half the thickness until the further penetrationof water would cause the disintegration of the hydrophilic layer andtherefore the release of the content which, consisting of lipophilicgranules, however induces the diffusional mechanism typical of thesestructures and therefore further slows down the dissolution profile ofthe active ingredient.

The following examples illustrate the invention in greater detail.

EXAMPLE 1

770 g of 5-aminosalicylic acid are added in a kneader with 20 g ofcarnauba wax and 50 g of stearic acid with heating until homogeneousdispersion, then extruded into small granules while cold.

The inert matrix granules are loaded into a mixer in which 30 g ofCarbopol 971P^((R)) and 65 g of hydroxypropyl methylcellulose aresequentially added.

After a first mixing step for homogeneously dispersing the powders, 60 gof microcrystalline cellulose and 5 g of magnesium stearate are added.After mixing, the final mixture is tabletted to unitary weight of 649mg/tablet or 510 mg/tablet to obtain 500 and 400 mg dosages,respectively.

The resulting tablets are film-coated with cellulose acetophthalate orpolymethacrylates and a plasticizer to provide gastric resistance andprevent the early release of product in the stomach.

The dissolution profile of these tablets shows the release of an activeingredient amount lower than 30% within the first hour of permanence insimulated enteric juice, an amount lower than 60% at the fourth hour andan amount lower than 90% at the eighth hour, thus proving that thedouble matrix effectively controls dissolution.

EXAMPLE 2

1000 g of 5-aminosalicylic acid are added in a kneader with 10 g ofcarnauba wax and 20 g of stearic acid with heating until homogeneousdispersion, then extruded into small granules while cold or directlygranulated in a high rate mixer.

The resulting granules are loaded into a mixer in which 80 g ofhydroxypropyl methylcellulose and 12 g of sodium starch glycolate aresequentially added. After a first mixing step, 11 g of silica colloidaland 11 g of magnesium stearate are added. The final mixture ishomogenized, then tabletted to a unitary weight of 1144 mg/tablet.

The resulting tablets are then film coated with polymethacrylates orcellulose acetophthalate and plasticizers to provide gastric resistance.

The dissolution profile of these tablets after a lag time of permanencein the stomach and partly in the intestine provides the release of nomore than 30% within the first hour, no more than 55% within two hours,no more than 70% within four hours, no more than 90% within eight hours.

EXAMPLE 3

850 g of 5-aminosalicylic acid are added in granulator/kneader with 9 gof beeswax and 22 g of palmitic acid with heating, until homogeneousdispersion; then worked to a granulate in a high shear granulatingdevice. The resulting granules are then loaded into a mixer which isadded in succession with 45.5 g of hydroxypropyl methylcellulose, 45.5 gof microcrystalline cellulose, 20 g of sodium starch glycolate, 22 g ofcolloidal silica and 22 g of magnesium stearate. After homogenization,the final mixture is tabletted to a unitary weight of 975 mg/tablet.

The resulting tablets are then film coated with polymethacrylates oracetophthalate of cellulose and plasticizers to provide gastricresistance.

The dissolution profile of these tablets after a lag time of permanencein the stomach and partly in the intestine provides the release of nomore than 30% within the first hour, no more than 50% within two hours,no more than 70% within four hours, no more than 90% within eight hours.

EXAMPLE 4

1100 g of 5-aminosalicylic acid are added in granulator/kneader with 10g of wax carnauba and 20 g of stearic acid.

10 g of polyacrylamide, 39.5 of microcrystalline cellulose and 22 g ofcolloidal silica are separately loaded into the homogenizer/granulatorto obtain a homogeneous solid mixture, which is placed in the mixerwhere the active ingredient has been granulated and homogenized. 49.5 gof hydroxypropyl methylcellulose and 12 g of sodium alginate arethoroughly mixed, then added with 5 g of calcium carbonate, 34.5 g ofmicrocrystalline cellulose and 11 g of magnesium stearate. The mixtureis homogenized, then tabletted to a final unitary weight of 1194mg/tablet. The resulting tablets are then film-coated withpolymethacrylates or cellulose acetophthalate and plasticizers toprovide gastric resistance.

The dissolution profile of these tablets after a lag time of permanencein the stomach and partly in the intestine provides the release of nomore than 35% within the first hour, no more than 50% within two hours,no more than 70% within four hours, no more than 90% within eight hours.

EXAMPLE 5

1200 g of 5-aminosalicylic acid are added in mixer with 10 g of carnaubawax and 20 g of stearic acid, with heating until homogeneous dispersion,then cold extruded into small granules or directly granulated in thehigh rate mixer. The resulting granules are loaded into a mixer, then 70g of hydroxypropyl methylcellulose and 20 g of sodium starch glycolateare sequentially added.

After a first mixing step, 80 g of sodium carbonate and 5 g of magnesiumstearate are added. The final mixture is homogenized, then tabletted tounitary weight of 1375 mg/tablet.

The resulting tablets are then film-coated with polymethacrylates orcellulose acetophthalate and plasticizers to provide gastric resistance.

The dissolution profile of these tablets after a lag time of permanencein the stomach and partly in the intestine provides the release of nomore than 30% within the first hour, no more than 50% within two hours,no more than 70% within four hours, no more than 90% within eight hours.

What is claimed is:
 1. Controlled-release oral pharmaceuticalcompositions containing as an active ingredient 5-amino-salicylic acid,comprising: a) an inner lipophilic matrix consisting of substancesselected from the group consisting of unsaturated and/or hydrogenatedfatty acid, salts, esters or amides thereof, fatty acid mono-, di- ortriglycerids, waxes, ceramides, and cholesterol derivatives with meltingpoints below 90° C., and wherein the active ingredient is dispersed bothin said the lipophilic matrix and in the hydrophilic matrix; b) an outerhydrophilic matrix wherein the lipophilic matrix is dispersed, and saidouter hydrophilic matrix consists of compounds selected from the groupconsisting of polymers or copolymers of acrylic or methacrylic acid,alkylvinyl polymers, hydroxyalkyl celluloses, carboxyalkyl celluloses,polysaccharides, dextrins, pectins, starches and derivatives, alginicacid, and natural or synthetic gums; c) optionally other excipients;wherein the active ingredient is present in an amount of 80 to 95% byweight of the total composition, and wherein the active ingredient isdispersed both in the lipophilic matrix and in the hydrophilic matrix.2. Compositions as claimed in claim 1, wherein 5-aminosalicylic acid isdispersed in a molten lipophilic matrix by kneading, extrusion and/orgranulation.
 3. Compositions as claimed in claim 1, in the form oftablets, capsules, mintablets.
 4. A process for the preparation of thecompositions of claim 1, which comprises: a) melt granulation of atleast one portion of the active ingredient with the lipophilicexcipients with melting point lower than 90° C.; b) mixing the granulesfrom step a) with the hydrophilic excipients and subsequent tablettingor compression.